Each year, about 600,000 American suffer from stroke. Thrombolytic therapy with tissue plasminogen activator (tPA) is the only FDA-approved medicine for achieving both vascular reperfusion and clinical benefit, but only 2-5% of stroke patients receive tPA in the US. In part, this because tPA therapy unfortunately increases the risk of intracerebral hemorrhage by approximately 10-fold. Perhaps even more importantly, there is accumulating evidence from experimental models and clinical studies that tPA can have neurotoxic actions separate from its beneficial clot lysis properties, tPA neurotoxicity may further exacerbate ischemic brain damage, particularly in the 50% of patients who have no perfusion improvement after receiving intravenous tPA.
Many clinical trials attempting to provide neuroprotection following stroke have failed. While, to date, tPA-based thrombolytic therapy is the only FDA-approved treatment for achieving vascular reperfusion and clinical benefit, this agent is given to only about 2-5% of stroke patients (25, 26). This may be related, in part, to the elevated risks of symptomatic intracranial hemorrhage, and a short therapeutic time window in order to decrease the clinical risk of tPA's limitations. Specifically, tPA therapy limitations include: (1) short 3 hr treatment time window, (2) risk of intracerebral hemorrhage, and (3) neurotoxicity. Others have tried to find other lytics with equal thrombolysis properties for safe and effective reperfusion at longer times after stroke onset. One example is the vampire bat saliva molecule desmoteplase. However, the recent completion of a desmoteplase (DIAS-2) clinical trial failed. So the problem of a safe and effective use of tPA in the treatment of stroke remains unsolved.
What is needed is a composition and method that increases the thrombolytic efficacy of tPA, while reducing neurotoxicity and the risk of hemorrhagic transformation.